Drug addiction is characterized by a blunted response to non-drug incentives and rewards. This attenuation appears to be especially pronounced when addicted individuals anticipate that drug use soon will be possible. Non-human animal studies indicate that there are large individual differences in the extent to which non-drug rewards are devalued when drug delivery is expected. Moreover, animal research suggests that several clinically-relevant aspects of addictive behavior are predicted by individual differences in the expectancy- related devaluation of non-drug rewards. To date, individual differences in the effects of drug use expectancy on the processing of non-drug rewards, and the functional correlates of such individual differences, have not been investigated in human drug users. The goal of this proposal is to address this knowledge gap by examining the nature and implications of individual differences in the effects of drug use expectancy on neural responses to non-drug rewards in human smokers (n=60). The specific aims of the proposed research are: 1) To examine the effects of a novel within-subjects smoking expectancy manipulation on neural responses to non-drug (i.e., monetary) rewards in human smokers;and 2) To examine how individual differences in the effects of smoking expectancy on neural responses to non-drug rewards relate to the ability to resist smoking in order to obtain an incentive. We hypothesize that individuals will vary significantly in the degree to which non-drug rewards are devalued when drug use is anticipated. As the ability of non-drug incentives to serve as an effective reinforcer for abstinence behavior likely depends substantially upon the extent to which they maintain their value in the face of an opportunity to use drugs, we also hypothesize that individual differences in the expectancy-induced devaluation of non-drug rewards will be predictive of the capacity to refrain from smoking in order to obtain money. This proposal serves as an initial step towards a long-term research plan aimed at investigating the reward-processing biases that play an important role in maintaining addictive behavior. Specifically, if our predictions are supported, future studies will extend the proposed research by seeking to identify variables that modulate the expectancy-related devaluation of non-drug rewards (e.g., the magnitude and delay of the non-drug reward), elucidating approaches for minimizing reward devaluation within individuals (e.g., individually tailored incentives), and examining changes in expectancy-related devaluation associated with the implementation of such approaches. PUBLIC HEALTH RELEVANCE: Cigarette smoking remains one of the leading preventable causes of death and disease in the world. Accordingly, developing a better understanding of the motivational factors that underlie the maintenance of nicotine addiction and, ultimately, how to more effectively treat the disorder will have substantial public health benefits. Moreover, results from this project will be applicable to several other disorders characterized by aberrant motivational processing (e.g., other substance use disorders, eating disorders).